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A kind of preparation method of high-purity sofosbuvir compound and related substances

A technology of sofosbuvir and sofosbuvir, which is applied in the field of preparation of high-purity sofosbuvir, can solve the problems of affecting the cost and yield of finished products, difficult to separate removal, etc., and achieves easy operation, high purity, SF-P low content effect

Active Publication Date: 2017-06-16
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] As stated in the invention patent application CN201180017181.3, the impurity is similar to sofosbuvir in polarity, and it is difficult to remove it, requiring chromatographic separation, which will inevitably affect the cost and yield of the finished product

Method used

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  • A kind of preparation method of high-purity sofosbuvir compound and related substances
  • A kind of preparation method of high-purity sofosbuvir compound and related substances
  • A kind of preparation method of high-purity sofosbuvir compound and related substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (SF-1)

[0038] Weigh 100 g of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate and dissolve it in 15 times the volume of anhydrous MeOH, add 0.75eq MeONa, the reaction solution was heated to reflux, reacted for 2-4 hours, and the raw materials were completely reacted. Cool the reaction solution to about 50°C, add 3 times the amount of strongly acidic cationic resin (H type) to the reaction solution, and stir for about 15 minutes until the pH of the reaction solution is about 6-6.5. The reaction solution was filtered, and the filter cake was washed with an appropriate amount of MeOH. The filtrates were combined and concentrated to dryness under reduced pressure. Add 10 times the volume of MTBE to the residue, reflux the slurry for 2 hours, cool to room temperature, filter, rinse, and vacuum-dry the target product (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine , 99.8% purity.

Embodiment 2

[0041] Example 2: Preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (SF-1)

[0042] Weigh 400 g of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate and dissolve in 15 times the volume of anhydrous MeOH, add 1eq MeONa, the reaction solution was heated to reflux, reacted for 2-4 hours, and the raw materials were completely reacted. Cool the reaction solution to about 50°C, add 3 times the amount of strongly acidic cationic resin (H type) to the reaction solution, and stir for about 15 minutes until the pH of the reaction solution is about 6-6.5. The reaction solution was filtered, and the filter cake was washed with an appropriate amount of MeOH. The filtrates were combined and concentrated to dryness under reduced pressure. Add 10 times the volume of MTBE to the residue, reflux the slurry for 2 hours, cool to room temperature, filter, rinse, and vacuum-dry the target product (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine , 99.7% purity.

Embodiment 3

[0043] Embodiment 3: the preparation of sofosbuvir

[0044] Under the protection of nitrogen, 20 g of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine prepared in Example 1 was added to the reaction bottle, and 15 times the volume of Anhydrous THF, the temperature of the reaction solution was lowered to -5°C, 2.15eq of t-BuMgCl was added dropwise to the reaction solution, and the addition was completed, the reaction solution was stirred at -5°C for 1 hour, then raised to 20°C, stirred for 2 hours, then, the reaction Cool the liquid to about 0°C, add N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl to the reaction liquid The THF solution of the ester (1.2eq) was added completely, and the reaction solution was reacted at 5°C-7°C for about 20 hours. The reaction solution was cooled to 0°C, and 2N HCl solution was added to quench the reaction, then, 25 times the volume of toluene was added to the reaction solution for extraction, and the liquids were separated...

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Abstract

The invention belongs to the technical field of medicine, and provides a method for preparing high-purity sofosbuvir, using easily available SF-2 as a raw material, deprotecting with MeONa to generate a key intermediate SF-1, and then combining with phosphoric acid ester The side chains are connected, and the high-purity target product sofosbuvir can be obtained after treatment, especially the impurity SF-P content is extremely low. The present invention innovatively uses MeONa as a deprotection reaction reagent, and uses a strong acidic resin to remove alkali during post-treatment, simplifies the production process, and obtains the key intermediate SF-1, which has a higher purity and yield; and In the process of preparing sofosbuvir, a new post-treatment method is used to obtain high-purity sofosbuvir API.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of high-purity sofosbuvir, in particular to a preparation method of high-purity sofosbuvir with extremely low impurity SF-P content. Background technique [0002] Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver diseases such as cirrhosis and liver cancer. There are a large number of infected individuals, estimated at 2-15% of the world's population. Current treatments for HCV infection are limited by Immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin has achieved limited clinical benefit. Furthermore, a vaccine for HCV has not yet been established. Therefore, there is an urgent need for improved therapeutic agents that are effective against chronic HCV infection. [0003] The drug sofosbuvir is the first drug to safely and effectively treat certain types of hepatitis C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H19/073C07H1/00G01N30/02
Inventor 郭璇柴雨柱徐丹杨治旻田舟山张健曹标
Owner NANJING CHIA TAI TIANQING PHARMA
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